Lymphomas in Prof Paul Ruff Division of Medical Oncology

Lymphomas in 2010 Prof Paul Ruff Division of Medical Oncology

Most Common Lymphomas: ~90% B-cell and ~10% T-cell T lymphoblastic: 2% Marginal zone, nodal: 2% Other: 9% Burkitt: 2% Anaplastic large cell: 2% Diffuse large B cell: 31% Mediastinal large B cell: 2% Mantle cell: 6% Small lymphocytic/cll: 7% Peripheral T cell: 7% Marginal zone, extranodal: 8% Follicular: 22% Armitage JO, et al. J Clin Oncol. 1998;16:2780-2795.

B- Cell Lymphoproliferative Disorders (~90%) Low Grade : CLL/SLL Follicular Marginal Mantle Cell Hairy Cell Leukaemia High Grade : Diffuse Large B-Cell B-Lymphoblastic/ALL Burkitt s Lymphoma Multiple Myeloma

Lymphomas: Ann Arbor Staging (1971) Stage I: One lymph node group Stage II: >1 lymph node group on same side of diaphragm Stage III: Lymph nodes on both sides of diaphragm Stage IV: Extralymphoid spread eg. marrow, lung, liver, brain A/B: presence or absence of symptoms: Night sweats, repeated fever >38ºC, >10% weight loss

Staging of Lymphomas Radiological staging essential for prognostic and therapeutic reasons Chest X-ray Spiral Chest CT if CXR suggests mediastinal or hilar adenopathy Spiral CT head and neck also be needed in some lymphoma patients MRI brain needed in AIDS lymphomas

Staging of Lymphomas Spiral CT abdomen and pelvis essential today Ultrasound sub-optimal for retroperitoneal structures and in obese patients Lymphangiogram obsolete but was used in Hodgkin s lymphoma pre-1990s when CT scanning was limited and inadequate Staging laparotomy no longer important with advent of better chemotherapy and reduced role of radiation in Hodgkin s lymphoma?role of 18 FDG PET/CT scan in staging newly diagnosed patients

Staging of Lymphomas: Follow-up Spiral CT chest/abdomen to assess extent and size of lymph glands during and after completion of chemotherapy +/- radiation Exact tumour size essential in clinical trials Residual glands may not be malignant therefore a 18 FDG PET/CT scan very useful to define active tumour tissue versus residual fibrosis

Follicular NHL Common indolent NHL 24,000 new cases diagnosed annually in USA Rising in incidence Variable clinical course Incurable with standard therapy; multiple remissions and relapses Histological transformation Median survival improving t(14;18)(q32;q21) Oncogene: bcl-2

Follicular Lymphoma Classification Grade Grade 1 Grade 2 Grade 3 3a 3b Characteristic 0-5 centroblasts/hpf 6-15 centroblasts/hpf > 15 centroblasts/hpf Centrocytes present Solid sheets of centroblasts Blood. 1997;89:3909-3918.

FLIPI Prognostic Score Characteristic RR (Death) Older than 60 yrs of age 2.38 Stage III-IV 2.00 Hemoglobin < 12.0 g/dl 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39 FLIPI and OS Risk Group Risk Factors, n 5-Yr OS, % 10-Yr OS, % Low 0-1 91 71 Intermediate 2 78 51 High 3 53 36 Solal-Céligny, et al. Blood. 2004;104:1258-1265.

Predictive Power of Gene Expression Signature in Follicular Lymphoma Expression Signature (Prognosis) RR of Death P Value Immune response 1 (favorable) 0.15 <.0001 Immune response 2 (unfavorable) 9.35 <.0001 Dave SS, et al. N Engl J Med. 2004;351:2159-2169.

Follicular Lymphoma: Indications for Therapy Cytopenias secondary to bone marrow infiltration Threatened end-organ function Symptoms attributable to disease Bulk at presentation Steady progression during > 6 mos of observation Presentation with concurrent histologic transformation Massive splenomegaly Patient preference Candidate for clinical trial

Treatment Options in 2010: Observation (watch and wait) Radiation Single-agent therapy Combination chemotherapy Interferon-α Monoclonal antibodies: especially rituximab Hematopoietic transplantation Antisense molecules Vaccines Targeted agents

Monoclonal Antibodies in B-Cell Lymphoma Rituximab: Naked chimeric monoclonal antibody against CD20 antigen CD20 on cell surface of most B-cell malignancies except primitive B-cell ALL and post-mature myeloma cells Licensed as Mabthera (RSA/Europe) or Rituxan (USA) in CD20+ B-cell lymphomas

Key features of Rituximab Chimeric anti-cd20 MoAb CD20+ cell Activates complement mediated cytotoxicity & antibody dependent cellular cytotoxicity (ADCC) Direct anti-tumor effects Human Mouse Synergistic activity with chemotherapy Sensitizes chemoresistant cell lines

CVP versus CVP + Rituximab for Stage III-IV Follicular Lymphoma R A N D O MI Z AT IO N CVP arm Wks 1 4 7 10 13 16 19 22 Observation R-CVP arm Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.

CVP versus CVP + Rituximab for Advanced Follicular Lymphoma Outcome CVP CVP + Rituximab CR, % 10 41 Duration of response, mos 14 38 4-yr survival, % 77 83 Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.

Prolonged Survival With Chemo + Rituximab for FL CVP vs R-CVP [1] CHOP vs R-CHOP [2] MCP vs R-MCP [3] 1. Marcus R, et al. J Clin Oncol. 2008;26:4579-4586. 2. Hiddemann W, et al. Blood. 2005;106:3725-3732. 3. Herold M, et al. J Clin Oncol. 2007;25:1986-1992.

Overall Survival (%) Improving Survival of Follicular NHL: Impact of Antibody-Based Therapy 100 80 OS by Treatment 1990s-2000s 60 1990s 40 20 4-Year N Death Estimate CHOP + Mab 179 18 91% ProMace 425 189 79% CHOP 356 226 69% 0 0 2 4 6 8 Years After Registration Reprinted with permission. 2008 American Society of Clinical Oncology. All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23:8447-8452. 10 1980s

Treatment of FL: Summary Rituximab prolongs PFS and OS in patients requiring treatment Despite progress, relapsing patterns continue to be observed Maintenance rituximab improves PFS Longer-term follow-up will be of interest to determine whether there is a survival advantage Many unanswered questions Role of watchful waiting Role of maintenance therapy Role of FLIPI or risk stratification in choosing therapy

Potential Antibody Targets for B-Cell Lymphomas CD23 CD37 CD40 CD52 CD74 CD80 CD22 Death receptors CD20 HLA-DR CD19 CD5 Surface immunoglobulin B cell Cheson BD, et al. N Engl J Med. 2008;359;613-626. Copyright [year of publication] Massachusetts Medical Society. All rights reserved.

New Antibodies for Follicular Lymphoma Antibody Epratuzumab (humanized) Ofatumumab (human) Galiximab (chimeric) Dacetuzumab (humanized) Inotuzumab-ozogamicin (humanized) Veltuzumab (humanized) GA-101 (humanized) Type Anti-CD22 Anti-CD20 Anti-CD80 Anti-CD40 Anti-CD22 Anti-CD20 Anti-CD20

Rituximab-Refractory Indolent NHL Patients treated with rituximab who then Fail to respond to rituximab therapy Progress within 6 months of rituximab therapy In the US, often includes patients refractory to an R- chemo regimen or who progress during maintenance therapy Outcome of this group of patients has not been well evaluated, and optimal therapy is unknown

Rituximab-Refractory Indolent NHL: Standard Therapy Options Radioimmunotherapy On label Response rate high, time-to-progression variable ASCT Randomized trial suggests benefit over standard therapy Applicable to minority of patients May be difficult with extensive previous therapy or marrow involvement AlloSCT Potentially curative option High transplantation-related mortality and morbidity Donor a requirement

Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment clinicaloptions.com/oncology

Diffuse Large B-Cell Lymphoma Most common NHL: 31% Peak incidence in 6th decade Curable in 50% or more of cases Median survival: wks to mos if not treated Clinical outcomes and molecular features highly heterogeneous Large cells with loss of follicular architecture of node 30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms May present as extranodal disease (stomach, CNS, testis, skin) Michallet AS, et al. Blood Rev. 2009;23:11-23.

DLBCL: Prognostic Factors (IPI) Risk Group Patients (all ages) Risk Factors, n CR, % 5-Yr OS, % Low 0-1 87 73 Low intermediate 2 67 51 High intermediate 3 55 43 High 4-5 44 26 Patients 60 yrs of age or younger Low 0 92 83 Low intermediate 1 78 69 High intermediate 2 57 46 High 3 46 32 Adverse risk factors correlated with response to chemotherapy and survival Older than 60 yrs of age LDH > normal PS 2 Ann Arbor stage III/IV Extranodal involvement > 1 site* *Prognostic for patients older than 60 yrs of age only. International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.

Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL Diffuse Large B- Cell Lymphoma Dave SS, et al. N Engl J Med 2006;354:2431-2442. Copyright (2006) Massachusetts Medical Society. All rights reserved.

OS Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL Diffuse Large B- Cell Lymphoma 1.0 0.8 0.6 0.4 DLBCL Subgroup 5-Yr OS, % PMBL 64 GCB DLBCL 59 ABC DLBCL 30 0.2 0 0 2 4 6 8 10 Yrs Rosenwald A, et al. J Exp Med. 2003;198:851-862. Originally published in The Journal of Experimental Medicine.

Probability DLBCL Subtype Retains Prognostic Value With R-CHOP Therapy CHOP-Rituximab OS CHOP-Rituximab PFS CHOP OS 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0 P = 4 x 10-3 0 1 2 3 4 5 6 0.2 0 P = 1 x 10-4 0 1 2 3 4 5 6 0.2 0 P = 8 x 10-6 0 1 2 3 4 5 6 Yrs Yrs Yrs GCB DLBCL ABC DLBCL Lenz G, et al. N Engl J Med. 2008;359:2313-2323.

DLBCL Treatment Localized stage I/II disease: Abbreviated course of chemotherapy with immunotherapy followed by radiation or a full course of chemotherapy Advanced-stage disease: Chemoimmunotherapy plus combination of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy for 6-8 cycles NCCN practice guidelines in oncology: non-hodgkin s lymphomas V.1.2010. Available at: http://nccn.org/professionals/physician_gls/pdf/nhl.pdf.

SWOG 8736: CHOP ± Radiotherapy in NHL in Localized DLBCL (Stage I and II) Stratified by age (< vs 65 yrs), histology (DLBCL vs others), disease site (GI vs other), stage (I vs II), resection of all visible tumors (y vs n) Untreated patients with localized intermediate/high grade NHL (N = 401) CHOP q3w for 3 cycles (n = 200) CHOP q3w for 8 cycles (n = 201) IFRT Endpoints: PFS, OS, toxicity Miller TP, et al. N Engl J Med. 1998;339:21-26.

OS (%) SWOG 8736: OS for DLBCL Patients Treated With CHOP ± Radiotherapy 100 80 60 40 Death, 5-Yr 20 N n Estimate, % CHOP + RT 152 53 82 CHOP 149 61 71 0 0 3 6 9 12 Yrs After Registration Miller T, et al. ASH 2001. Abstract 3024.

CHOP ± Rituximab in Advanced-Stage DLBCL: GELA LNH-98.5 Phase III Study Stratified by center and risk factors (0-1 vs 2-3) Assessment Untreated elderly patients with stage II-IV DLBCL (N = 399) R-CHOP q3w for 8 cycles (n = 202) CHOP q3w for 8 cycles (n = 197) Primary endpoint: EFS Secondary endpoints: OS, RR Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126.

Probability of EFS Overall Probability of Survival CHOP ± Rituximab in DLBCL: 3-Yr Survival Results (GELA LNH-98.5 Study) EFS OS 1.0 1.0 0.8 CHOP plus rituximab 0.8 CHOP plus rituximab 0.6 0.6 0.4 CHOP 0.4 CHOP 0.2 P <.001 0.2 P =.007 0 0 0 0.5 1.0 1.5 2.0 2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs After Randomization Pts at Risk, n CHOP plus 202 177 137 108 63 19 rituximab CHOP 197 144 101 72 42 17 Yrs After Randomization Pts at Risk, n CHOP plus 202 187 167 118 64 21 rituximab CHOP 197 171 136 96 58 16 Coiffier B, et al. N Engl J Med. 2002;346:235-242. Copyright (2002) Massachusetts Medical Society. All rights reserved.

Survival Probability CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study) 1 OS (N = 399) CHOP 0.8 R-CHOP 0.6 0.4 0.2 0 P =.0004 0 1 3 5 7 8 2 4 6 Yrs Coiffier B, et al. ASCO 2007. Abstract 8009.

MInT: Phase III Study of CHOP-like Chemo ± Rituximab in Adv. DLBCL (Younger Pts) Cycle 6 Patients with untreated CD20+ stage II-IV DLBCL (or bulky stage I), IPI 0-1, 18-60 yrs of age (N = 823) CHOP-Like Regimen* + 30-40 Gy radiotherapy (n = 410) Stratified by age-adjusted IPI score (0 vs 1), bulky disease, treatment center, and regimen CHOP-Like Regimen* + Rituximab 375 mg/m 2 + 30-40 Gy radiotherapy (n = 413) *CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO. Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.

Impact of Rituximab: The MInT Trial Group For rituximab plus chemotherapy vs chemotherapy alone, the impact of rituximab that was demonstrated in the GELA trial also held true in the MInT trial with benefits in: EFS PFS OS Pfreundschuh M, et al. Lancet Oncology. 2006; 7: 379-391.

Diffuse Large B-Cell Lymphoma: Nodal Response Before Treatment After Treatment

Guideline Recommendations for Treatment of Relapsed DLBCL Second-line therapy in candidates for high-dose therapy + ASCT DHAP ± rituximab ESHAP ± rituximab GDP ± rituximab GemOx ± rituximab ICE ± rituximab MINE ± rituximab Second-line therapy for patients who are not candidates for high-dose therapy Clinical trial Rituximab CEPP ± rituximab Lenalidomide EPOCH ± rituximab NCCN practice guidelines in oncology: non-hodgkin s lymphomas V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.

PARMA Study: ABMT vs Conventional Chemotherapy in Relapsed NHL Patients with chemosensitive NHL (int or high grade) in 1st or 2nd relapse following doxorubicin regimen and CR to initial induction regimen Bone marrow harvest Sensitive (n = 109) BEAC ± RT (n = 55) ABMT (N = 215) D H A P D H A P Resistant (n = 90) DHAP ± RT (n = 54) Salvage Tx ABMT Philip T, et al. N Engl J Med. 1995;333:1540-1545.

EFS (%) OS (%) PARMA Study: Bone Marrow Transplantation versus Salvage Chemotherapy 100 100 Transplantation Conventional treatment 80 80 60 60 40 40 20 0 P =.001 0 15 30 45 60 75 90 20 0 P =.038 0 15 30 45 60 75 90 Mos After Randomization Mos After Randomization Philip T, et al. N Engl J Med. 1995;333:1540-1545. Copyright (1995) Massachusetts Medical Society. All rights reserved.

Investigational Therapies for DLBCL Bevacizumab: recombinant, humanized, monoclonal anti-vegf antibody Epratuzumab: humanized, monoclonal anti-cd22 antibody Everolimus: mtor inhibitor Lenalidomide: immunomodulator, antiangiogenic Radioimmunotherapy Tamatinib: inhibitor of Syk in B-cell signaling pathway Bortezomib: proteasome inhibitor Enzastaurin: PKCβ-selective inhibitor

DLBCL Treatment: Summary Eminently curable with chemoimmunotherapy approaches, both for patients with limited-stage disease and for those with advanced-stage disease/localized stage I/II disease Modern era treatment Combination of rituximab and chemotherapy, typically using the R-CHOP for an abbreviated course of therapy plus radiation for patients with limited-stage disease or possibly R-CHOP for 6-8 cycles for those patients without radiation For patients with advanced-stage disease, R-CHOP chemotherapy for 6-8 cycles total NCCN practice guidelines in oncology: non-hodgkin s lymphomas V.1.2010. Available at: http://nccn.org/professionals/physician_gls/pdf/nhl.pdf.

PET to Determine Treatment Approach in DLBCL Following 3 R-CHOP Cycles Retrospective analysis of PET-guided treatment in patients with limited-stage DLBCL Median follow-up: 20 months Patients from BC Cancer Lymphoid Database aged 16 years with newly diagnosed, limited-stage DLBCL and biopsy proven disease (N = 50) R-CHOP x 3 PET Neg (n = 37) PET Pos R-CHOP x 1* (n = 13) IFRT *1 patient received subsequent IFRT because of chemotoxicity and 1 died prior to receiving further therapy. Sehn LH, et al. ASH 2007. Abstract 787.

Percent Survival PET to Determine Treatment Approach in DLBCL Following 3 R-CHOP Cycles Progression-Free Survival 1.0 PET negative 0.8 PET positive 0.6 0.4 0.2 0 0.5 1.0 1.5 2.0 2.5 Years Sehn LH, et al. ASH 2007. Abstract 787.

Mantle Cell Lymphoma: Clinical Features Accounts for ~ 6% of B-cell NHL cases Moderately aggressive course 74% male Median age: 63 yrs > 90% stage III/IV, including marrow involvement Extranodal sites common GI (upper and lower, can present as lymphomatous polyposis coli) Leukemic phase, PB flow commonly positive Armitage JO. Oncology (Williston Park). 1998;12(10 suppl 8):49-55. Fisher RI, et al. Hematology Am Soc Hematol Educ Program. 2004:221-226. O Connor OA, et al. Leuk Lymphoma. 2008;49(Suppl 1):59-66.

MCL: Pathology CD20 CD5 Cyclin D1 BCL2 Typical immunophenotype: CD20+, CD5+, CD23-, CCND1+, FMC7+, BCL2+ Morphological variants Diffuse histology: 75% Nodular: 10% to 15% Mantle zone: 5% to 7% Blastoid: 5% t(11;14)(q13;q32) CCDN1 driven by IgH locus Occasion amplification; CCDN2 or CCDN3 translocation

MCL: Critical Role of Cyclin D1 100 80 60 H&E H&E OS (%) 40 All patients Cyclin D1+ Cyclin D1- P =.0002 20 0 0 5 10 15 Yrs Cyclin D1 This research was originally published in Blood. Yatabe Y, et al. Blood. 2000;95:2253-2261 the American Society of Hematology. Cyclin D1 Most cases of lymphoma that are CD20+, CD5+, and CD23- and lack expression of cyclin D1 are not MCL but rather variant CLL

Improvement of OS in MCL During the Last Decade Median OS of patients with advanced MCL significantly increased from 2.7 to 4.8 yrs (HR: 0.44; P <.0001) 5-yr survival increased from 22% to 47% Patients with advanced MCL benefit from progress in medical treatment Rituximab? New agents? Aggressive therapy with transplant? Herrmann A, et al. J Clin Oncol. 2009;27:511-518.

MCL: Conventional Therapy CHOP ± rituximab Median FFS: 15-18 mos Few long-term survivors Howard and colleagues [1] showed improved CR with rituximab but no improvement in PFS Fludarabine Lower response rate than CHOP, similar FFS Highly active when combined with cyclophosphamide but increased toxicity 1. Howard OM, et al. J Clin Oncol. 2002;20:1288-1294.

SWOG 0213: HyperCVAD + Rituximab in Newly Diagnosed MCL Multicenter, nonrandomized, prospective, phase II trial Recruited October 2002-September 2006 (N = 49) 8 cycles of hypercvad (fractionated cyclophosphamide, vincristine, doxorubicin, + dexamethasone) alternating every 21 days with rituximab + high-dose methotrexate/ cytarabine Prophylactic anti-infectious agents, G- CSF given Disease type Nodular: 3 (6%) Diffuse: 13 (27%) Mantle zone: 28 (57%) Blastic: 4 (8%) Too early: 1 (2%) Stage III/IV disease: 49 (100%) Zubrod performance status 0: 29 (59%) 1/2: 20 (41%) Epner EM, et al. ASH 2007. Abstract 387.

Percentage of Patients SWOG 0213: HyperCVAD + Rituximab in Newly Diagnosed MCL 100 Survival Outcomes 80 Overall survival 60 Progression-free survival 40 20 Survival Outcome At Risk, n Progression/Death, n 1-Year Estimate, % Progression-free 49 13 89 Overall 49 9 91 0 0 1 2 3 4 5 Epner EM, et al. ASH 2007. Abstract 387. Years From Registration 6

PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL Open-label, prospective, international, multicenter, phase II trial Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 of 21-day cycle Upon CR/CRu Treatment continued for 4 additional cycles If no CR/CRu Treatment continued up to 17 cycles or until disease progression or toxicity Characteristic Median age, years (range) Median time from diagnosis, yrs (range) Patients (N = 155) 65 (42-89) 2.3 (0.2-11.2) Median prior therapies 1 Stage IV MCL, % 77 IPI score 3, % 44 KPS < 90%, % 29 LDH > upper limit of normal, % 36 Bone marrow involvement, % 55 Goy A, et al. ASH 2007. Abstract 125.

Event-Free Probability PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL 1.0 0.8 Time to Progression Median Time to Progression CR/CRu: not yet reached PR: 9.1 months All patients: 6.7 months 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 Time (Months) Goy A, et al. ASH 2007. Abstract 125.

Conclusions Lymphomas are amongst the most curable adult malignancies Predominantly B-cell phenotype (~90%) CHOP-type chemotherapy standard since 1970s Radiation useful in localized disease Advent of rituximab, a chimeric anti-cd20 monoclonal antibody has revolutionized the treatment of most B-cell lymphomas T-cell lymphomas have a more aggressive course and are more difficult to treat. Evolving role of 18 FDG PET/CT scanning in monitoring lymphoma treatment